Infection: A Disaster Movie for Gut Microbes?

Imagine if your comfortable existence was suddenly and traumatically disrupted by a disaster. Your home is destroyed, food becomes scarce, and social structures suddenly break down. Even the most civilized people would respond to this situation with desperation, doing whatever it takes to survive in the short-term without the usual considerations for the long term.

Now imagine you are a bacterium, living inside the human gut (this might take a bit more imagination). For as long as you can remember, everything has been cool there – a steady stream of nutrients pass by to feed on, the police force of the body’s immune system does not perceive you as a threat, and a happy society has been established with the thousands of other bacterial species in the area. But suddenly, the world as you know it is shaken. The human in which you have made your home contracts a serious illness, and undergoes surgery and intense antibiotic treatment. Millions of your fellow citizens are killed, the food supply dries up, the immune system declares martial law. Facing this desperate situation, bacteria tend to act just like humans would – they riot.

This pattern of ecological collapse leading to chaos may underlie one of the most difficult problems facing health care today: hospital infections. Since surgeon Joseph Lister discovered in the 1860’s that carbolic acid can be used to sterilize surgical instruments and wounds to reduce infection rates, hospitals have grown obsessed with cleanliness to protect patients from bacterial invasion. Yet even perfect diligence cannot prevent serious infections from occurring in a small population of patients, causing scientists such as John Alverdy, professor of surgery at the Medical Center, to ask: Could the threat of bacterial infection be coming from within?

“It’s a new way of thinking about infection, because we’re already doing already we can – washing our hands, sterilizing the site, giving our patients antibiotics – and yet some of the infections seem to be getting worse,” Alverdy said. “There has to be a strategy change, and I think we’re at the forefront of understanding that.”

Alverdy’s group has spent the last decade studying a member of the gut microbiome (the world of bacteria living inside our digestive system), called Pseudomonas aeruginosa. Most of the time, Pseudomonas is a passive colonizer of the human body, an “accidental pathogen” that we pick up through our diets or other environmental exposure that causes no harm. But when the body is severely stressed by a surgical procedure, illness, chemotherapy, or radiation, Pseudomonas occasionally panics and becomes an extremely dangerous inhabitant. Alerted to the body’s emergency by immune system factors and starved for food, it begins tunneling through the lining of the gut to invade the unfortunate patient’s blood. Once the bacteria goes on the attack, it’s very difficult to treat, giving it the highest mortality rate of any hospital infection.

“I have seen some people postulate that Pseudomonas isn’t a very virulent pathogen, and I say ‘what are you talking about?’,” Alverdy said. “If you provoke it the right way, it will kill everything in its wake. It’s very virulent.”

In multiple papers, Alverdy and his collaborators have discovered multiple signals that trigger the alarm system of Pseudomonas, such as the immune factor interferon gamma or low levels of the essential nutrient phosphate. Each bacterial cell possesses multiple sensors to detect these changes, and when the environment becomes too disrupted and unhealthy, it activates weapons to desperately fight for life. What seems like a paradoxical response – destroying one’s home – might actually be a smart, long-term plan for some microbes, Alverdy said.

“You kill your host, because it’s doing you no good, it’s not resource-rich, you’re trapped inside of it, and if you kill it you’ll have enough to feed off, for a long time. A dead carcass is a lot of food, and then something else might eat it also, and you’ll jump to a new host. That’s one explanation,” Alverdy said. “Pseudomonas is trigger-happy and it’s short-sighted.”

The near-term hope for an intervention would be to somehow maintain “healthy” levels of any alarm-tripping signals in a patient weakened by surgery, illness or treatment, in order to trick Pseudomonas and other gut bacteria into remaining docile. Protection could come in the form of a gel that coats the person’s body, or a drink that can line the walls of the gut. Unlike the traditional method of slaughtering both good and bad bacteria with prolonged antibiotics to treat or prevent infection, this strategy is almost environmental: it’s about keeping the body’s bacterial ecosystem happy, nourished, and calm.